Antihyperglycemic methods and compositions

ABSTRACT

The blood sugar level of hyperglycemic animals can be reduced through administration of an N1-phenylbiguanide which is substituted in the N5-position by the group CH2R2 in which R2 is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms, cyclohexyl or vinyl, and optionally substituted by one or two groups in the phenyl ring. Solid, orally administered pharmaceutical compositions are also described. A typical embodiment is the use of N1-(4-chlorophenyl)-N5-(npropyl)biguanide hydrochloride which can be administered in a tablet, capsule or dragee.

United States Patent Kabbe et al.

1*Apr. 22, 1975 ANTIIIYPERGLYCEMIC METHODS AND COMPOSITIONS Inventors:Hans-Joachim Kabbe, Leverkusen;

Harald I-Iorstmann, Wuppertal-Elberfeld; Hans Plumpe,Wuppertal-Elberfeld; Walter Puls, Wuppertal-Elberfeld; SiegfriedPetersen, Leverkusen, all of Germany Notice: The portion of the term ofI this patent subsequent to Sept. 19, 1989, has been disclaimed.

Assignee: Bayer Aktiengesellschaft,

Leverkusen, Germany Filed: Jan. 16, 1973 Appl. No.: 324,218

Related US. Application Data Continuation-in-part of Ser. No. 118,958,Feb. 25, 1971, abandoned, and Ser. No. 120,332, March 2, 1971,abandoned.

Foreign Application Priority Data Mar. 3, 1970 Germany 2009738 Mar. 3.1970 Germany 2009743 U.S. Cl. 424/326 Int. Cl. A6lk 27/00 Field ofSearch 118/958; 120/332; 426/326 56] References Cited UNITED STATESPATENTS 2,961,377 1 1/1960 Shapiro et a1 424/326 3.689.674 9/1972 Kabbeet al 424/326 FOREIGN PATENTS OR APPLICATIONS 581.346 10/1946 UnitedKingdom 424/326 649,692 1/1951 United Kingdom 426/326 OTHER PUBLICATIONSChemical Abstracts, Vol. 41, (1947), 16264628; Vol. 43, (1949), 5868;Vol. 44, (1950) 6032.

Primary E.raminer-Frederick E. Waddel] [57] ABSTRACT 14 Claims, NoDrawings ANTIHYPERGLYCEMIC METHODS AND COMPOSITIONS CROSS-REFERENCE Thisis a continuation-in-part of Ser. No. 118,958, filed Feb. 25, 1971, andSer. No. 120,332, filed Mar. 2, 1971 now abandoned.

DETAILED DESCRIPTION The present invention pertains to a method oftreating hyperglycemia and to solid, orally administerablepharmaceutical compositions for use in this treatment.

As a result of the extensive work of Curd and coworkers, a wide varietyof biguanides were prepared as potential antimalarial agents; see forexample British patent specification Nos. 577,843; 599,714; 603,069;603,070; 607,720; 618,613; 624,540; and 667,094. This extensive programled to the development of compound No. 4888 which isN-(4-chlorophenyl)-N isopropylbiguanide or proguanil. This compoundpossessed unique action on the preerythrocytic and erythrocytic forms ofa number of species of avian malaria parasites and has been used sincethat time in the treat ment of malaria. Curiously there is substantialevidence that the compound itself has little effect on the malariaparasite and Hawkins et al., Brit. J. PharmacoL, 3, 320 (1948) havesuggested that it is transformed by the body into a different activespecies. At present, it is believed that this active species may becycloguanide which is l(4-chlorophenyl)-2,2-dimethyl-4,6-diamino*1,2-dihydro-l,3,5-triazine. In actual use, proguanil is administered tohumans for therapeutic purposes at doses in the range of 300 mg per day,generally through the administration of 100 mg tid. In an examination ofthe toxicity and general pharmacology of proguanil, Chen et al. noted aslight blood sugar depressing effect. J. Pharmacol. Exp. Therap., 91,157 1947). The slight hypoglycemic effect of the compound was notconsidered remarkable by Chen et al. and occurred only at a doseapproaching the toxic dose and well above the therapeutic dose of thecompound when utilized for the treatment of malaria. The poorantidiabetic effect of N'-ary1-N -alkylbiguanide has also been observedby Elpern, Ann. N.Y. Acad. Sci., 148,577 (1968).

The present invention is based upon the discovery that a specific classof N -phenyl-N -substituted biguanides possess remarkableanti-hyperglycemic action at doses far lower than would have beenexpected from the work of Chen et al. and indeed far lower than thedoses contemplated for such compounds as proguanil when utilized in thetreatment of malaria. In particular, the present invention pertains tothe method of achieving a hypoglycemic effect, in particular aantihyperglycemic effect, through administration of an effective amountof a biguanide of the formula:

NH NH R 1| 1 uu-c-mr-c-mtcl -a wherein each of R and R, independent ofthe selection of the other, is selected from the group consisting ofhydrogen,

alkyl of 1 to 6 carbon atoms, alkoxy of l to 6 carbon atoms, chloro,fluoro and bromo, and

R is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxyalkyl having a totalof 2 to 5 carbon atoms, cyclohexyl or vinyl, or an equivalent amount ofnontoxic acid addition salt thereof.

In addition, the present invention provides a solid, orallyadministerable composition adapted for use in the foregoing method oftreating hyperglycemia, which composition comprises a pharmaceuticalcarrier in admixture with a unit dosage amount of from about 5 to about55 mg of the above specified biguanide or an equivalent amount of anon-toxic acid addition salt thereof.

In view of the findings of Chen et al., supra, concerning proguanil, themost active of the N -phenyl-N substituted biguanides in terms ofantimalarial effect, it is totally unexpected that compounds of theabove formula should demonstrate such outstanding antihyperglycemiceffects and do so at extremely low and non-toxic levels. Moreover, incomparison with known biguanides which are commercially available asantidiabetic agents, such as n-butylbiguanide and N,N-dimethylbiguanide, the compounds utilized in the present invention canbe administered for therapeutical purposes at lower doses and superiortherapeutic ratios.

The compounds utilized in the present invention can be prepared forexample through the reaction of an appropriately substituted anilinewith a dicyanodiamide. Alternatively, an amine of the formula R Nl-l canbe reacted with a phenyl dicyanodiamide. Finally, it is possible toprepare the compounds utilized in the present invention through thereaction of a thio or dithiobiuret, or an S-alkyl derivative thereofwith an appropriately substituted aniline, amine or ammonia.

1n the method of the present invention, a biguanide as herein defined isadministered to effect an antihyperglycemic response. As with anyhypoglycemic agent, the specific dosage and dosage regimen must in eachcase be carefully adjusted to the recipient, utilizing soundprofessional judgement and taking into consideration the age, weight andconditions of the recipient, the nature and gravity of the illness andthe response observed in the specific individual. in general, ahypoglycemic effect can be observed utilizing a daily dose of from 2.5to 10 mg/kg. In some instances, a hypoglycemic effect can be obtained ata lower dose while in others, a larger dose may be required. Preferably,the biguanide is administered in a single daily dose although it canalso be divided into two, three or more doses per day. The route ofadministration is oral and such administration can be effected utilizingsolid dosage unit forms such as powders, tablets, dragees, capsules andthe like. These can be formulated so as to provide a sustained releasepattern. These solid dosage unit forms intended for oral administrationwill comprise the biguanide in an amount of from 0.5 to of the totalcomposition together with a pharmaceutical carrier which is non-toxic,inert and pharmaceutically acceptable. Other therapeutic agents can alsobe present but in general no advantage is observed in administering twotherapeutic agents in a single dose over individual administration ofthe two agents.

Powders are prepared by comminuting the biguanide to a suitably finesize and mixing with a similarly comminuted pharmaceutical carrier suchas an edible car bohydrate, as for example starch, lactose, sucrose,glucose or mannitol. Sweetening, flavoring, preservative and/or coloringagents can also be present Capsules are prepared by filling formedgelatin sheaths with a powder mixture, prepared as above. Glidants andlubricants such as colloidal silica, talc, magnesium stearate, calciumstearate and/or solid polyethylene glycol can be added to the powdermixture before the filling operation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can beadded to improve the availability of the medicament when the capsule isingested.

Tablets are formulated by preparing a powder mixture, granulating orslugging, adding a lubricant, optionally with a disintegrant, andpressing into tablets. A powder mixture is prepared by mixing thecompound with a solid diluent, as described above, and optionally with abinder such as carboxymethylcellulose, an alginate, gelatin orpolyvinylpyrrolidine. In addition, a solution retardant such asparaffin, a resorption accelerator such as a quaternary salt and/orabsorption agent such as bentonite, kaolin or dibasic dicalciumphosphate can be included. The powder mixture is granulated by wettingwith a binder such as syrup, a starch paste, acacia mucilage orsolutions of cellulosic or polymeric materials and forcing the massthrough a screen. Alternatively, the powder mixture can be run through atablet machine and the resulting imperfectly formed slugs broken intogranules. These granules can be lubricated to prevent sticking by meansof the addition of stearic acid, a stearate salt, talc or mineral oiland the lubricated mixture is then compressed into tablets. In someinstances, the medicament can be combined with a free flowing inertcarrier and compressed directly into tablets without going through agranulating or slugging step. The biguanide can also be mixed ,with alow melting solid such as a mixture of hydrogenated castor oil andglycerin monostearate in a melt to form a matrix which may then bepressed into tablets or coated with an outside layer of active material.A protective coating, which may be clear or opaque, such as shellac,sugar or a polymeric material may also be provided and a final polishcoating of wax can then be applied. Dyestuffs can also be added to thesecoatings to distinguish different dosage unit forms or origin ofmanufacture.

As noted above, prolonged or sustained release formulations are alsoincluded in these compositions and can be'achieved throughmicroencapsulation, or by coating or embedding particulate material inpolymers, wax or the like.

Although these solid oral dosage unit forms can contain from 5 to asmuch as 100 mg of biguanide, generally the amount will be from about 5to about 55 mg and most preferably about 30 mg of biguanide per singledosage unit form.

The desired anti-hyperglycemic effect of the compounds utilized in thesecompositions can be conveniently observed in well known and conventionalanimal models. Thus for example the test compound is administered orallyto fasting rats at several dosage levels. After several administrations,a solution of glucose in physiological saline is administered per s. Theblood glucose level of the animal is measured 30 to 60 minutes afteradministration of the glucose and the dose which causes a significant (P0.05) reduction in byperglycemia is recorded. Typical results are asfollows (for the hydrochlorides except as otherwise noted).

" naphthalcncl .S-disulfonalc The toxicity of the compounds utilized inthe present method and composition is also favorable.

N Substitucnt N Substitucnt LD (Rat mg/kg) 4-methylphcnyl n-propyl 198n-butyl 87 isobutyl 302 3-methylphcnyl n-butyl 57 3 3,4-dimcthylphenyln-butyl 600 isobutyl 28 8 4-ethylphenyl n-propyl 208 n-butyl 204isobutyl 23 3 B-methoxycthyl 420 4-n-butylphenyl n-pentyl 1000 phenyln-butyl 25 6 isobutyl 636 4-mcthnxyphenyl isobutyl 808 3-mcthoxyphcnyln-butyl 45 2 isobutyl 55 2' 4-chlorophenyl n-propyl I20 I n-butyl 320isobutyl 38 2 n-pentyl 45 2 n-propyl 7l 4-fluorophcnyl isobutyl 367naphthalene-l.5-disulfonatc in mouse In contrast to the above, proguanilas the hydrochloride demonstrates anti-hyperglycemic activity at 10mg/kg but has an LD of 114 mg/kg in the rat. The known n-butyl biguanidedemonstrates antihyperglycemic activity at 16 mg/kg with an LD of 220mg/kg in the rat.

The following examples will serve to further typify the nature of thisinvention but should not be construed as a limitation thereof, theinvention being defined solely by the appended claims.

EXAMPLE I A mixture of 18.8 g 4-ethylphenyldicyanodiamide and 8.2 gethylamine hydrochloride is heated at C.

for 1 hour. The resultant oil is dissolved hot in I00 ml isopropanol andupon'coolin'g, there are obtained 15.6

1 5 g (58%) N -(4-ethylphenyl)-N -ethylbiguanide hydro- Continuedchloride, m.p. 165 167C.

EXAMPLE 2 N Substituent N5 Substituent Melting Point (HCl) A mixture of17.4 g 5-methylphenyldicyanodiamide 5 any] lgmgfioc and 16.6 gn-octylamine hydrochloride is reacted as den-butyl 21 1-212C scribed inExample 1. There are thus obtained 16.2 g isobutyl 239-2403: (48%) N-(4-methylphenyl)-N -n-octylbiguanide as 21333 "$338 C thehydrochloride, m.p. 183 185C. n-octyl 190-l91C 1O B-methoxycthyl 165- 167C EXAMPLE 3 3-chlorophenyl isobutyl 212-214C 4-bromo hen l nent'll99-20lC A mixture of 16 g p-anisidine hydrochloride and 14 p y p y gn-butyldicyanodiamide is stirred at 160C for 2 hours. Upon dissolvingthe product in isopropanol and cooling there are obtained 11.3 g (34%)of the hydrochloride 15 EXAMPLE 6 l 5 Salt of o N YP Y Y Conversion ofthe hydrochloride salt of N -(4- 186 chlorophenyl)-N -propy1biguanide tothe free base and treatment with naphthalene-l,S-disulfonic acid ieldsEXAMPLE 4 h d h h l 5 d If y l t e corres on in na t a ene-l isu onatesa t, A mixture of 13.9 g N-p-tolyl-N -n-pentylguanyl thio- 0 o p o g pmp 169 -171 C.

urea, 12 g mercury oxide and 100 ml of 17% ammonia in methanol isstirred in a pressure vessel at 50C for 6 EXAMPLE 7 hours' Insolublemimer removed by filtrallon The following formulations are specificembodiments under suction and the filtrate is concentrated, mixed ofpharmaceutical compositions in which the biguanide with ml of 2Nhydrochloric acid and concentrated 25 s can be any of those set forthabove: again. The residue is recrystallized from isopropanol to yield 6g (38%) N -(4-methylphenyl)-N -n-pentyl biguanide (compound 6) in theform of the hydrochloride, m.p. 215C. A Tablet Ingredient Amount/TabletEXAMPLE 5 Biguanidc 30 mg. [n a similar fashion to that described inExamples Lactose 99 mg, 1-3, disubstituted biguanides, which aredescribed by Starch 60 I Talcum 10 mg. analogous chemical terminology,are obtained. Magnesium stearate 1 mg 200 mgv N Substitucnt N5Substitucnt Melting Point (HCl) The biguanide, lactose and half thequantity of maize phcnyl mpmpyl ZOLZOQOC 40 starch are mixed, kneadedtogether with a paste of one n-butyl 206208C quarter of the quantity ofmaize starch. This mass is i pressed through a sieve with 3 5 mm. meshsize, and Z1 4 methy|phcny| ethyyl 303 204C dried at 60 80C. The drygranulate is forced through -g p y a sieve with 0.8 mm. mesh width, andthe remaining figgjl 227:2396C maize starch, talcum and magnesiumstearate are p y mixed in. The composition is pressed mto round tabletsg fjg 21 8 220C of 8 mm. diameter and total weight of 200 mg. with tab-'y-ethoxypropyl 185-187C let press, 3-mcthylphcnyl n-hutyl 188C3.4-dimcthylphcnyl n'hutyl 207209C isobutyl l94l95C 5O 4-cthylphcnyln-propyl 160C n.butyl 196-198C B Tablet isobutyl 22 l-222C y l 96CIngredient Amountfl'ablet cyclohexylmethyl 205-207C 4'(n-butyl)phcnyln-butyl 193C Bi 7 30 I, o guani 0 mg.

f [86488; Dibasic calcium phosphate 97 mg. 4-tcrtbutylphcnyl isobutyl217-219 C G 7 m 4-fluorophcnyl isobutyl 238C I h 6 isopemyl 2| 15Cagncsium stearate mg 4-methox hen l ethyl 162-164C 150 mg.

" yp y n-propyl 169-171C isobutyl 207-209c 6Q S-mcthoxyphenyl n-butyl168l70C I I isobuty {$1225 The biguanide and calcium phosphate aremixed, 4'e.ihoxyphcnyl kneaded with an aqueous solution of gelatin,sieved Y- p y y ggi-ggfg through a 3 to 5 mm mesh and dried at to C. The

isobuty 3-chloro-4-meth0Xyp enyl isobutyl 20140; 65 dry granulate isresieved through 0.8 mm mesh. The 3-methoxy-4-methylphcnyl isigbutyl133-13 wheat starch and magnesium stearate are mixed in and3-chloro-4-meth l henyl nutyl z g 4mm 180C the resultant compositionformed into round tablets of 213-214C mg having a diameter of 7 mm.

4chlorophenyl ri-propyl C Delayed Release Two-layer Dragee lngredicntAmount/Dragee Nucleus Biguanidc mg.

Dibasic calcium phosphate 82 mg.

Gelatin 2 mg.

Wheat starch mg.

Magnesium stearate l mg 10 I20 mg.

40% l7( 0. l I1 I07: ad 100% Biguanide Sugar Gum arabic Gelatin TalcumWater When the applied layer contains 15 mg biguanide per dragee. thedragee is sealed with several layers ofa suspension of:

Sugar 607: Gum arabic l)? Gelatin 0.1% Talcum 10% Water ad 100% to therequired final weight. Edible dye can be added to the syrup at thispoint and the dragees glazed or polished with glazing wax. These drageesrelease the first half of the the biguanide dose (15 mg) immediately inthe stomach and the second half only in the intestine.

D Delayed Release Wax-matrix Tablets lngredient Amount/Tablet 5OBiguanide 30 mg. Hydrogenated castor oil 60 mg. Glycerin monostcarate 10mg I00 mg.

E Capsules Ingredient Amount/Capsule Biguanide 30 mg. Dibasic calciumphosphate 1 16 mg. Magnesium stcarate 3 mg. Colloidal silicic acid l mgThe ingredients are mixed and filled into hard gelatin capsules.

F Capsules lngredient Amount/Capsule Biguanide 30 mg. Lactose 60 mg.Polyvinylpyrrolidonc 3 mg. Stearic acid 1 mg. Colloidal silicic acid Img. Talcum 5 mg The biguanide and lactose are mixed, kneaded with asolution of polyvinylpyrrolidone and stearic acid in methylene chloride,sieved (3 5 mm) and dried (50 60C). The dry granulate is forced througha sieve with mesh width of 0.5 0.6 mm. Colloidal silicic acid and talcumare mixed in, and the resultant composition is filled with a suitableapparatus into hard gelatin capsules.

Alternatively, the wax granulate described in Example 7!), instead ofbeing tabletted, can be introduced into hard gelatin capsules to providecapsules with delayed release of the biguanide.

What is claimed is:

l. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animala. blood sugar lowering amount of a component of the formula 11a in 2NE- mt NHCHZ a or a pharmaceutically acceptable non-toxic acid addior apharmaceutically acceptable non-toxic acid addition salt thereof whereinone of R and R is hydrogen and the other is 4-methyl, and R is isobutyl.

3. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula I l NE- --NH"NECK R or a pharmaceutically acceptable non-toxic acid addition saltthereof wherein one of R and R is hydrogen and the other is 3-methyl,and R is n-butyl.

4. A method of reducing the blood sugar level in a hy perglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula flu Ha un--mrmicu R2 or a pharmaceutically acceptable non-toxic acid addition saltthereof wherein one of R and R is hydrogen and the other is 4 ethyl, andR is n-propyl.

5. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula I E NH== ==NH=.unen R2 or a pharmaceutically acceptable non-toxic acid addition saltthereof wherein one of R and R is hydrogen and the other is 4ethyl, andR is n-butyl.

6. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula or apharmaceutically acceptable non-toxic acid addition salt thereof whereinone of R and R is hydrogen and the other is 4-ethyl, and R is isobutyl.

7. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula Ha NH- c-uauucuR2 or a pharmaceutically acceptable non-toxic acid addition salt thereofwherein R and R are both hydrogen, and R is isobutyl.

9. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula or apharmaceutically acceptable non-toxic acid addition salt thereof whereinone of R and R is hydrogen and the other is 3-methoxy, and R is n-butyl.

10. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula i i NH' NH--uuca R2 or a pharmaceutically acceptable non-toxic acid addition saltthereof wherein one of R and R is hydrogen and the other is 3-methoxy,and R is isobutyl.

11. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula i i NH- -NHNHCH2- R2 or a pharmaceutically acceptable non-toxic acid addition saltthereof wherein one of R and R is hydrogen and the other is 4-chloro,and R is n-butyl.

12. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula or apharmaceutically acceptable non-toxic acid addition salt thereof whereinone of R and R is hydrogen and the other is 4-chloro, and R is isobutyl.

13. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula 3" l Nil- -NH--Nl'lCH R or a pharmaceutically acceptable non-toxic acid addition saltthereof wherein one of R and R is hydrogen and the other is 4-fluoro,and R is isobutyl.

1. A method of reducing the blood sugar level in a hyperglycemic humanor animal which comprises orally administering to such human or animal ablood sugar lowering amount of a component of the formula
 1. A METHOD OFREDUCING THE BLOOD SUGAR LEVEL IN A HYPERGLYCEMIC HUMAN OR ANIMAL WHICHCOMPRISES ORALLY ADMINISTERING TO SUCH HUMAN OR ANIMAL A BLOOD SUGARLOWERING AMOUNT OF A COMPONENT OF THE FORMULA
 2. A method of reducingthe blood sugar level in a hyperglycemic human or animal which comprisesorally administering to such human or animal a blood sugar loweringamount of a compound of the formula
 3. A method of reducing the bloodsugar level in a hyperglycemic human or animal which comprises orallyadministering to such human or animal a blood sugar lowering amount of acompound of the formula
 4. A method of reducing the blood sugar level ina hyperglycemic human or animal which comprises orally administering tosuch human or animal a blood sugar lowering amount of a compound of theformula
 5. A method of reducing the blood sugar level in a hyperglycemichuman or animal which comprises orally administering to such human oranimal a blood sugar lowering amount of a compound of the formula
 6. Amethod of reducing the blood sugar level in a hyperglycemic human oranimal which comprises orally administering to such human or animal ablood sugar lowering amount of a compound of the formula
 7. A method ofreducing the blood sugar level in a hyperglycemic human or animal whichcomprises orally administering to such human or animal a blood sugarlowering amount of a compound of the formula
 8. A method of reducing theblood sugar level in a hyperglycemic human or animal which comprisesorally administering to such human or animal a blood sugar loweringamount of a compound of the formula
 9. A method of reducing the bloodsugar level in a hyperglycemic human or animal which comprises orallyadministering to such human or animal a blood sugar lowering amount of acompound of the formula
 10. A method of reducing the blood sugar levelin a hyperglycemic human or animal which comprises orally administeringto such human or animal a blood sugar lowering amount of a compound ofthe formula
 11. A method of reducing the blood sugar level in ahyperglycemic human or animal which comprises orally administering tosuch human or animal a blood sugar lowering amount of a compound of theformula
 12. A method of reducing the blood sugar level in ahyperglycemic human or animal which comprises orally administering tosuch human or animal a blood sugar lowering amount of a compound of theformula
 13. A method of reducing the blood sugar level in ahyperglycemic human or animal which comprises orally administering tosuch human or animal a blood sugar lowering amount of a compound of theformula